Viral respiratory tract infections are among the leading causes of hospitalization, economic loss, and mortality in the US and worldwide. With the continued threat from emerging pathogens as well as complications from more common respiratory viruses, understanding these infections and their accompanying host responses remain a major priority for global public health. In particular, efforts must also be made to understand these infections within the context of an aging population. While modern germ theory has greatly reduced its burden, infectious disease remains the fourth leading cause of death in aging adults. Coupled with the robust increase in aged populations over the next two decades, these factors highlight the importance of understanding the interplay between infection and the senescent host. While significant progress has been made in understanding the age-related deficiency in adaptive immunity, much less is understood about tissue specific and innate immune cell function in the aging host. Therefore, these studies take a systems based approach to characterize and examine the early tissue-specific and innate immune responses to respiratory virus infection within the context of aging. Utilizing severe acute respiratory syndrome coronavirus (SARS-CoV), the proposal seeks to compare young, middle-aged, and aged mice in order to identify, confirm, and validate major change in pathway and immune activation that contribute to enhanced susceptibility and can be exploited for therapeutic treatment. In addition, the project extends examination into primary human airway and immune cells in order to confirm and validate in vivo finding. Finally, efforts will be made to explore th contribution of broad epigenetic changes to differential responses in young and aged models. Together, these approaches will yield important findings critical to understanding and treating current and future respiratory virus infections in aged populations.